Operating regimes of signaling cycles: statics, dynamics, and noise filtering.
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These results are obtained using the total quasi-steady-state approximation, which is more generally valid than the typically used Michaelis-Menten approximation for enzymatic reactions.Numerical simulations show that our analytical results hold well even for noise of large amplitude.We suggest that noise filtering and tunability make signaling cycles versatile components of more elaborate cell-signaling pathways.
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PubMed Central - PubMed
Affiliation: Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
ABSTRACT
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A ubiquitous building block of signaling pathways is a cycle of covalent modification (e.g., phosphorylation and dephosphorylation in MAPK cascades). Our paper explores the kind of information processing and filtering that can be accomplished by this simple biochemical circuit. Signaling cycles are particularly known for exhibiting a highly sigmoidal (ultrasensitive) input-output characteristic in a certain steady-state regime. Here, we systematically study the cycle's steady-state behavior and its response to time-varying stimuli. We demonstrate that the cycle can actually operate in four different regimes, each with its specific input-output characteristics. These results are obtained using the total quasi-steady-state approximation, which is more generally valid than the typically used Michaelis-Menten approximation for enzymatic reactions. We invoke experimental data that suggest the possibility of signaling cycles operating in one of the new regimes. We then consider the cycle's dynamic behavior, which has so far been relatively neglected. We demonstrate that the intrinsic architecture of the cycles makes them act--in all four regimes--as tunable low-pass filters, filtering out high-frequency fluctuations or noise in signals and environmental cues. Moreover, the cutoff frequency can be adjusted by the cell. Numerical simulations show that our analytical results hold well even for noise of large amplitude. We suggest that noise filtering and tunability make signaling cycles versatile components of more elaborate cell-signaling pathways. Related in: MedlinePlus |
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Mentions: The four regimes we consider, although obtained only at extreme parameter values, are actually quite descriptive of the system for a wide range of parameters, and naturally partition the space of possible steady-state behaviors of the signaling cycle into quadrants, as shown Figure 3. Figure 3 shows the relative error between the steady-state characteristic of each of the four regimes and that of Equation 3 for a wide range of kinase and phosphatase MM constants (see Text S4). It reveals that the regime approximations are quite good at a wide range of values of MM constant (for example, the region with a relative error of less than 10% for each regime covers almost a full quadrant in the plots), and not only when the MM constants take the very large or very small values required in the regime definitions. This demonstrates that these four regimes, though defined by extreme values of system parameters, actually encompass the full space of cycle behaviors. |
View Article: PubMed Central - PubMed
Affiliation: Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.